The development of effective therapy for children with acute lymphoblastic leukemia (ALL) is one of the[unreadable] great successes of clinical oncology, with long-term survival achieved by over 80% of patients. However,[unreadable] therapy remains non-specific, toxic and sometimes lethal. Moreover, cure rates for adults with ALL[unreadable] remain relatively, low, with only 40% of patients cured. The goal of Project 6 is to maximize the[unreadable] therapeutic index (the efficacy:toxicity balance) in the treatment of ALL. We seek to increase cure rates,[unreadable] decrease acute and long-term morbidity, identify novel prognostic factors and perform clinical trials with[unreadable] new agents discovered within this Program Project. In Specific aim 1, we extend our successful clinical[unreadable] pediatric program to include adult patients (age 18-50 years), affording us the unique opportunity to[unreadable] directly compare uniformly treated adults and children in terms of response to therapy, toxicity and[unreadable] underlying biology. Specific aim 2 will seek to optimize dosing of asparaginase, a chemotherapeutic[unreadable] agent utilized in all regimens for adult and pediatric ALL, by determining the relative efficacy, toxicity and[unreadable] pharmacodynamics of intravenous polyethylene glycosylated (PEG) asparaginase and intramuscular[unreadable] native E.coli asparaginase. Specific aim 3 will explore the pathogenesis and pharmacogenomic[unreadable] predictors of doxorubicin cardiotoxicity by studying the association between cardiac outcome and[unreadable] mutations of mitochondrial DMA and/or hemochromatosis genes, and also continue our long-term[unreadable] assessment of doxorubicin cardiotoxicity, including the value of serial monitoring during treatment and[unreadable] the effects of continuous infusions of doxorubicin and dexrazoxane in preventing cardiomyopathy. We[unreadable] are committed to rapid translation of discoveries from Projects 1-5 and have already put that goal into[unreadable] action by conducting a Phase l/ll trial of gamma secretase inhibitors in children and adults with relapsed[unreadable] T-cell ALL. In Specific aim 4, we will continue to initiate innovative clinical trials of targeted[unreadable] therapies based on the findings from our laboratories, including not just the gamma secretase inhibitor[unreadable] trial, but also studies of the mTOR inhibitor, rapamycin, to enhance steroid-induced apoptosis, and novel kinase inhibitors, with the plan to incorporate active agents into upfront[unreadable] therapy for high risk patients aged 1-50 years.